Promoting the Science of Regulatory Statistics in Support of Regulatory Decisionmaking

1 August 2013717 viewsNo Comment

The ASA will celebrate its 175th anniversary in 2014. In preparation, column “175”—written by members of the ASA’s 175th Anniversary Steering Committee and other ASA members—will chronicle the theme chosen for the celebration, status of preparations, activities to take place, and, best yet, how you can get involved in propelling the ASA toward its bicentennial.

Contributing EditorRobert T. O’Neill is the senior statistical advisor for the Office of Translational Sciences in the Center for Drug Evaluation and Research at the Food and Drug Administration. He is a Fellow of the American Statistical Association and Society for Clinical Trials.

Reflecting on an exciting career and accepting the challenge

I began my career at the Food and Drug Administration (FDA) in July of 1971 as a new PhD with a theoretical background in mathematical statistics and biometry. However, my undergraduate training was in mathematics and the liberal arts, which has been critical to the development of my skill mix and I still believe is relevant to the modern statistician operating in a multidisciplinary world. Six years of Latin, languages, philosophy, history, the sciences, and the Jesuits will do that to you.

I came to FDA largely because of Chuck Anello, who recruited me. Chuck had recently assumed leadership of the statistics program and was building capacity of PhD-level statisticians to support the FDA after new regulations laid the framework for substantial evidence of efficacy for new drugs to enter the marketplace. This was new to everyone. There was no guidance, no process, and little history to build on, yet there was a lot of passion for doing something that would contribute to public health by using statistics.

Many thought there were no interesting statistical problems at FDA. I thought otherwise, and despite the fluctuating challenges, frustrations, and constraints placed on a government program throughout a 40-year period, it was one of the best places for a biostatistician to work and one that afforded any statistician willing to invest the effort with opportunities.

For me, it has been an exciting and challenging ride, as it has been for numerous statistical colleagues who have contributed to the accomplishments and statistical program that now exists to support the FDA’s Center for Drug Evaluation and Research. It also has been satisfying to see how my statistical colleagues developed and led the growth of regulatory statistical programs in other FDA centers responsible for the public health areas of biologics, medical devices, foods, and veterinary medicine. Review science is different from most other fields, few know about it until they experience it, and it is different from the other major areas of government-sponsored statistical programs that have survey sampling at their core.

The growth of the biostatistical program in the pharmaceutical area was fueled by a combination of public health crises that occurred over the years, the recognition that the science of statistics and applied statistics could help solve and/or address some of these regulatory issues, and the FDA’s willingness to provide human resources to support and build a program of professional statisticians that were strong in methodology, consulting, and negotiating and affecting drug regulatory decisions. The FDA regulatory environment is unique for statisticians in that the job entails quantitative and personal skills in planning, evaluation, data analysis, professional speaking, and interaction with the industry and academic statisticians and other scientists.

My recollection of the growth of the statistical program begins with the 10 or so PhD-level statisticians recruited by Anello in the early 1970s and continues with its expansion to about 160 statisticians today. This growth came about in response to a variety of regulatory needs in clinical trial design and evaluation, preclinical safety testing, and pharmaceutical manufacturing quality control and testing; observational study design analysis supporting epidemiological programs; and quantitative safety, post-approval life-cycle evaluation of drug safety, adverse event monitoring and surveillance, and active surveillance under the congressionally mandated Sentinel System.

The 1970s were mainly spent evaluating clinical trials and safety studies that were not usually well designed or analyzed. These evaluations led to developing written guidance for conducting protocol and regulatory reviews of a new drug application, providing advice to industry, documenting what was done, and assuring the quality of the reviews conducted by an increasing number of statisticians. Currently, there are 17 medical divisions encompassing every drug disease area.

The 1980s saw the development of guidance for industry, initial discussions about the use of data-monitoring committees in industry-sponsored studies, the advent of the AIDS crisis that led to new paradigms such as accelerated approval based on surrogate markers, and much more participation by patient advocates in drug development. As new responsibilities were placed upon FDA, new resources were provided to most FDA disciplines, including statisticians. This required the scaling up of the statistical program to several divisions that required statistician managers and leaders in all areas—a challenging job for any statistician, but one that provided FDA senior statisticians with the opportunity to lead and contribute in many ways, both internal and external to FDA.

The 1990s began another increase in resources from the Prescription Drug User Fee acts, which were able to support the infusion of new statisticians to the statistical program approximately every five years. The new millennium saw a new emphasis on safety assessment and the need for quantitative safety assessment skills, all in response to congressionally mandated responsibilities placed on FDA and studies from the Institute of Medicine and National Academy of Sciences.

Finally, as the statistical program grew in number of statisticians, it required some statisticians to take on the role of management and leaders to coordinate standards that could be equitably applied over all medical areas. As this experience base increased and the collaborative research interest of these statisticians in regulatory research increased commensurate with their influence at FDA, the last 15 years or so have witnessed a remarkable increase in published regulatory statistical research by FDA statisticians who, in my opinion, have contributed to a new field of regulatory statistics.

This occurred with analogous growth and contributions from industry statisticians who developed white papers, supported the scientific positions taken by the PhRMA organization and other professional societies, and contributed to an explosion of literature and journals devoted in large part to biopharmaceutical statistics.

FDA became transparent in how it performed its work, and because of various freedom of information laws and public advisory committee initiatives, external statistical advisors to FDA have been a major source of additional advice and perspectives on the evaluation of drug safety and efficacy. The long list of academic and other government statisticians who have served on FDA advisory committees attests to these contributions, information on which is available on FDA’s publically searchable website.

So, having begun in an era of poor prospectively planned study protocols, poorly designed paper case report forms, paper-based clinical trial reports and data sets and moving into an era with virtually everything electronically database oriented and connected, the modern statistician at FDA enjoys the best of all worlds, with access to data, tools, software, and intellectual power that is truly remarkable.

However, the job is no easier. The problems are more difficult, and the science and statistical design and analysis issues continually challenge, creating new opportunities for biostatisticians to lead. You might ask why I stayed for so long. Well, the answer is that there was never a dull moment, a lot of excitement from the daily statistical challenges, my decisions to accept increasing levels of responsibility, and the increasing satisfaction that what I was doing helped the entire biopharmaceutical statistical profession live up to the challenge and really contribute to the public health solutions. The path is set for at least another 40 years of exciting careers in regulatory statistics by those who are up to the challenge.

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